Familial male-limited precocious puberty (FMPP) is a form of isosexual precocious puberty in boys that is independent of the normal pubertal pathway involving LHRH. Signs of puberty usually appear by 3-4 years of age. The diagnosis is based on the presence of pubertal to adult levels of testosterone in conjunction with prepubertal levels of basal and LHRH-stimulated gonadotropins, and hyperplasia of Leydig cells. Molecular genetic studies have identified missense mutations of the human luteinizing hormone/chorionic gonadotropin receptor (hLHR) in patients with FMPP. The hLHR is a member of G protein-coupled receptors and transduces the signal of agonist binding via the interaction with G protein and biosynthesis of cAMP. In FMPP, the autosomal dominant gain-of-function mutations give rise to constitutive activation of the receptor resulting in ligand-independent production of intracellular cAMP and testosterone, leading to precocious sexual development. Despite the observation of cellular transformation and the development of neoplasms under the influence of constitutively activated mutant forms of some G protein-coupled receptors and several different G proteins, constitutive activation of the hLHR has not so far been linked to tumorigenesis. Thirty five years ago a Caucasian male was diagnosed at age 27 months to have idiopathic precocious puberty based on physical findings, accelerated bone age and a testicular biopsy showing advanced maturation. Later on the LHRH-independent nature of the precocious puberty in this patient was recognized and confirmed. Subsequently, the presence of a heterozygous constitutive activating mutation of the hLHR (Asp578Gly) was identified using polymerase chain reaction and nucleotide sequencing. At the age of 36 years the patient was found to have developed a seminoma. Exposure to high levels of testosterone from early infancy in this patient due to constitutive activation of the mutated hLHR suggests a possible causative role in the malignant transformation. Careful monitoring of FMPP patients to assure early recognition of potential testicular tumors appears warranted. This work was funded in part by NIH grant HD31553.